In the past 1.5 months, Resverlogix has presented three times an abstract containing very new and very interesting information about apabetalone's effects on farnesoid X receptor (FXR) in primary human hepatocytes.

"In PHH exposed for 24 hrs to RVX-208, FMO3 mRNA was lower by 40% but it also suppressed a transcriptional regulator of FMO3, farnesoid X receptor (FXR). BETi suppressed both FXR mRNA and protein within 6 hrs by >80% suggesting a direct effect of BETi on gene encoding FXR. Furthermore, ChiP data showed that BRD4, a BET protein, dissociated immediately from FXR gene upon exposure to RVX-208. Since BRD4 guides a complex containing RNA pol II along actively transcribed genes containing histones that are highly acetylated, dissociation of BRD4 from FXR DNA would halt transcription of this gene.....The rapid actions of BETi in dissociating BRD4 from FXR DNA suggests a direct effect of RVX-208 on transcription of this gene." 

FXR is a key transcription factor expressed in the liver, intestine and kidney whose endogenous ligands are bile acids and is involved in bile acid, lipid and glucose metabolism. 

https://www.ncbi.nlm.nih.gov/pubmed/16037564

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063452/

Many of the pathways that apabetalone affects (i.e. complement, coagulation, inflammation, fibrinogen, apoAI/HDL, glucose metabolism) are known to involve FXR. This does not mean that all of apabetalone's effects are being mediated by way of FXR. However, the recently reported ability of apabetalone to modulate FXR levels definitely highlights this node.

Importantly, partial inhibition of FXR in mice (i.e. heterozygous knockout mice) and humans (i.e. heterozygous carriers of loss of function mutations) doesn't appear to be harmful. It could be that apabetalone is "cooling" off some of these FXR driven pathways just enough to provide beneficial effect. However, suppressed levels of FXR may be relevant to the mild, but transient, transaminase elevations seen in some patients. Surely, the DSMB is paying close attention to liver signals and the DSMB reports to date haven't mentioned any liver issues,. Furthermore, back in Oct 2016 Dr. Sweeney presented at the R&D day that "Dr. Paul Watkins, former head of the FDA liver injury department has since joined the BETonMACE DSMB." No news is good news on the liver front.

I don't think this will be the last we hear about FXR.

BearDownAZ